Aminoacid esters of n-substituted hydroxyalkyl piperidines



United States Patent AMINOACID ESTERS OF N-SUBSTITUTED HYDROXYALKYL PIPERIDINES John H. Biel, Milwaukee, Wis., assignor to Lakeside Laboratories, Inc., a corporation of Wisconsin No Drawing. Application August 8,. 1956 Serial No. 602,917

7 Claims. (Cl. 260247.2)

This invention relates to hydroxyalkyl piperidiues. More particularly, this invention is concerned with novel aminoacid esters of hydroxyalkyl piperidines and methods of producing such compounds.

I have discovered and provide by this invention novel N,N-disubstituted amino lower monocarboxylic acid esters of N-substituted hydroxyalkyl piperidines of the formula groups, preferably lower alkyl-monocyclic. aryl groups,

like benzyl and phenethyl groups, lower alkene groups such as the allyl group and groups in which R and R are joined to form a heterocyclic ring, preferably of 5 or 6 atoms in the ring, such as pyrrolidino, piperidino and morpholino.

Compounds of the above formulae may be conveniently prepared as the free base by reacting an ester of the amino acid with the N-substituted hydroxyalkyl piperidine. This reaction may be represented as follows:

wherein R, R R R and R have the significance previdibenzylaminovaleric acid and the like. Lower alkyl esters of these compounds may be used in the reaction, and preferably the methyl and ethyl esters.

The reaction is conveniently carried out by contacting an ester of the aminoacid with the N-substituted hydroxyalkyl piperidine in the presence of an inert solvent such as n-heptane, methylcyclohexane or xylene. A small amount of an alkali metal alkoxide, such as sodium methoxide, is generally added to catalyze the reaction. About equimolar quantities of the reactancts are preferably used. Elevated temperatures such as the reflux temperatures are generally used. By removing the alcohol by-product formed in the reaction, it is induced to go to completion within a minimum of time. After the theoretical amount of alcohol is collected the reaction is considered completed. The desired product may be conveniently re-' acid such as a mineral acid like sulfuric acid or hydrochloric acid, or organic acids like maleic acid, fumaric acid, acetic acid 'or citric acid.

Quarternary ammonium salts may also be readily prepared by contacting the compoundswith alkyl and aralkyl esters of mineral and organic acids, preferably in the presence of a suitable organic solvent. Alkyl halides such as methyl bromide, ethyl iodide, methyl sulfate, benzyl chloride and propargyl bromide are representative compounds that may be used to form quaternary ammonium salts.

The novel compounds of this invention in the form of free bases or non-toxic acid addition salts are useful ously assigned and R is a hydrocarbon group, preferably a lower alkyl group.

Some N-substituted hydroxyalkyl piperidines which may be employed as starting materials are N-methyl-2- hydroxymethyl piperidine, N-ethyl-3-(Z-hydroxyethyl) piperidine, N-propyl-4-(Z-hydroxyethyl)piperidine, N- benzyl-3-(3-hydroxypropyl)piperidine, N-phenethyl-Z-( lhydroxybutyl)piperidine and the like.

Typical aminoacids which may be used, as esters, in the reaction are 3-morpho1inopropionic acid, 3-pyrrolidinopropionic acid, 3-piperidinopropionic acid, 2-dimethylaminoacetic acid, 3-dimethylaminopropionic acid, 4-dipropylamiuobutyric acid, diphenylaminoacetic acid, 5-

diuretic agents. The quaternary ammonium salts are potent, long-lasting hypotensive agents.

The following examples illustrate specific embodiments of the invention, but it is to be understood that these examples are for illustration only and are not to be considered as restricting the invention.

Example 1 N methyl 2 piperidylmethyl 3' morpholinopropionate, having the structure:

N in,

A mixture containing 32.7 g. (0.24 mole) of N-methyl- Z-hydroxymethylpiperidine, 41.5 g. (0.24 mole) of methyl morpholinopropionate, 1.2 g. of sodium methoxide and 325 cc. of n-heptane was refluxed with stirring. The methanol separated as soon as it was formed. After all the methanol had been collected the solvent was removed by distillation and the product separated by fractional distillation, B. P. -l41 C./O.8 mm., yield 45 g. (69%).

Analysis.-Calcd. for C H N O N, 10.37. Found: N, 10.16.

Example 2 N methyl-Z-piperidylmethyl-3'-morpholinopropionate bis-methobromide. To a solution of 10.8 g. (0.04 mole) the resulting mixture refluxed for 3 hours.

ofthebase (Examplei llin 60 cc. of isopropyl alcohol was added 15.2 g. (0.16 mole) of methyl bromide and A solid precipitated which was separated by filtration and recrystallized from ethyl alcohol, M. P. 188-189 C.; yield 14 g. (7

Analysis.-Calcd. for C H Br N O Br, 34.78; N, 6.09. Found: Br, 35.19;.N, 6.14.

Example 3 N methyl 3 piperidylmethyl NflN'-dimethylaminoacetate dimaleate:

. O I CHzOl1-CHN(OH:);-2CH.C0 H- C'H-C 02H OH; The basic ester was prepared as shown in Example. 1, by reactingN-methyl-3-hydroxymethylpiperidine.with methyl N,N-dimethylaminoacetate; 147-148" C./22 mm.;. N 1.4622. It was converted to the dimaleatesalt in iso propyl alcohol, M. P. 73-44 C.

The bis-methobromidesalt was also prepared;.M. P. 232-233 C. dec.

Various changes and modifications: of theim/ention can be made and, to theextent that suchvariationsine corporate the spirit of this invention, they are intended to be included within thescope. of-the appendedvclairns.

Whatis, claimed. is:

1'. A member of. the group. consisting. of compounds.

essentially of the. formula:

a ll and non-toxic acid addition and quaternary ammonium salts thereof, wherein R is a member of the group consisting of lower alkyl and phenyl-lower alkyl groups; R and R are lower alkylene groups, and R and R arev members of the group consisting of lower alkyl groups, phenyl groups, phenyl-lower alkyl groups, lower'alkene groups; and groupsin which R and R are joined to form with. acompoundi ofsth'e" formula O R H CR1-N wherein R is a lower'alkyl group, R is a member: of the group consisting of lower alkyl and phenyl-lower alkyl groups, R and R are lower alkylene groups, and'R and R are members of the group consisting of loweralk-yl groups, phenylgroups, phenyl-lower alkyl groups;

lower alkene groups, and groups in'which R and R are joinedto': form a mon'ocyclic heterocyclic group. of'the group: consisting of'themorpholino, piperidino and-pyrrolidino groups.

References Cited. in the file of this patent UNITED STATES PATENTS Papa Ian. 2,. 1951. 

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS ESSENTIALLY OF THE FORMULA
 3. A N - METHYL - 2 - PIPERIDYL-METHYL-3''MORPHOLINOPROPIONATE. 